Type 1 diabetes (T1D), also known as "juvenile diabetes", is one of the most common chronic diseases of childhood. T1D is characterized by autoimmune destruction of beta cells, the insulin-producing cells of the pancreas. Many different genetic factors contribute to its development, but environmental factors such as infection with viruses, including coxsackievirus B (CVB), may also be involved. Genome-wide association studies have led to the discovery of an association of specific variants of the human gene melanoma differentiation-associated gene 5 (MDA5) with the decreased risk for T1D. Additional population-based studies have further confirmed these associations. MDA5 is an innate immune receptor that mediates type I interferon (IFN) production following viral infection. We hypothesize that certain individuals are more prone to develop T1D following CVB infection because they have enhanced type I IFN responses that are mediated by MDA5. The goal of this project is to establish the mechanisms by which MDA5 contributes to the development of virus- induced diabetes. We will use three distinct approaches to establish how MDA5 influences islet function in the setting of viral infection: (1) we will use a transgenic and knockout mouse model of CVB-induced diabetes to assess the role of MDA5 in diabetes, (2) we will assess the role of MDA5 in a rat model of virus-induced diabetes, and (3) we will examine the role of MDA5 in type I IFN responses in human islets challenged with virus. Through these studies, we will advance our understanding of how innate immunity influences the disease course following viral infection and can predispose certain individuals towards T1D. PUBLIC HEALTH RELEVANCE: Coxsackie B virus (CVB) is a common virus that can cause a spectrum of human disease that ranges from mild symptoms to severe, sometimes deadly illness involving inflammation of the heart or inflammation of the pancreas. Infection with CVB has been associated with the development of type 1 diabetes. Genome-wide association studies have established a link between variants of melanoma differentiation associated gene 5 (MDA5) and type 1 diabetes. The goal of this study is to understand the mechanisms by which CVB interacts with MDA5, which recognizes viral RNA, and can predispose certain individuals towards developing type 1 diabetes.